866 official endorsement, for the Food and Drug Administration has proposed that an "unencumbered warning" of increased risk of cardiovascular death be prominently included in the "package insert" of all oral hypoglycaemic agents. This "unencumbered warning" would accept U.G.D.P. findings as established ; it would extend them to all other drugs and dosages; it would dismiss criticisms as invalid and it would make no reference to contradictory findings. In our view, this action would not only unfairly "slant" the evidence but would introduce, by selective promotion and suppression of evidence, something approximating to an official version of the truth. As well as being alien to the tradition of free scientific debate, it could have the effect of giving F.D.A. pronouncements the force of law. A physician departing from the officially sanctioned "correct" treatment of diabetes might well lay himself open
to
TABLE 11--COMPARISON OF CORRECTED WEIGHTS OF MALF AND OF FEMALE INFANTS WHO LATER DEVELOPED DIABETES WITH CONTROl INFANTS OF THE SAME SEX
malpractice litigation.
The oral
controversy is far from settled. Inthe agents are being overused and misused, more in some countries than in others, but this is the fate of all drugs in common use. It is a problem more likely to be solved by education than legislation. Of course, the public welfare is paramount, and legislative action is sometimes required, but when it is imposed on the basis of shaky evidence and in the face of bona-fide division of opinion it is unacceptable. H. KEEN Department of Medicine, R. J. JARRETT Guy’s Hospital Medical School, London SE1 9RT. J. H. FULLER
hypoglycaemic
contestably,
WEIGHT GAIN IN INFANCY AND SUBSEQUENT DEVELOPMENT OF DIABETES MELLITUS IN CHILDHOOD
SIR,-It has been shown that, at the time of onset of diabetes in childhood, diabetic boys may be taller than average for their age.’ This suggests that an endocrine disorder has preceded overt diabetes by a considerable time. There have also been case-reports of infants with hypoglycaemic episodes developing diabetes mellitus in later childhood.’ These observations led us to investigate the pattern of weight gain in infancy in a group of children who developed diabetes. The 105 families attending our children’s diabetic clinic were sent questionnaires asking them to retrieve information TABLE I.-STATE OF UNDRESS OF DIABETIC CHILDREN WHEN WEIGHED IN
INFANCY, AND WEIOHT DEDUCTED
6
AND
TO ACHIEVE CORRECTED WEIGHTS AT
12
weights of ihese diabetic children in infancy were com40 male and 40 female infants who were born with pared between 38 and 41 weeks of gestation and whose birth-weights were within two standard deviations of the mean. These 80 control infants were randomly selected from a larger group currently under study in Oxford for other purposes. The weights in infancy of the diabetic children and of the control infants are compared in table n. For the males the birth-weights of the two groups are similar; at 6 months the diabetic group is significantly heavier; at 1 year the diabetic group is heavier but this difference does not reach significance. The two groups of female infants are of similar birth-weight; at 6 months the weights are similar; at 1 year the diabetic group is significantly heavier. These data suggest that children who develop diabetes mellitus are heavier at certain stages in infancy. This could be the result of overfeeding. Alternatively it may be an early indication of hormonal imbalance-possibly a relative hyperinsulinism. This work
(J.D.B.) and
supported by the British Diabetic Association M.R.C. programme grant (M.O.).
was
an
Department of Pædiatrics, University of Oxford, John Radcliffe Hospital, Headington, Oxford.
J. D. BAUM M. OUNSTED M. A. SMITH
MONTHS
the weight of their diabetic children at birth, 6 months, and 12 months as recorded on their infant-welfare-clinic cards. We obtained information on the weights in infancy of 13 diabetic girls and 22 diabetic boys. We also asked the parents to record whether the infants had been weighed naked, partially dressed, or dressed when they were weighed, or alternatively to say they were uncertain. These replies are shown in table i. In order to compare these weights with control infants who were weighed naked, we substracted a correction factor 220 g (the weight of a good-quality terry-towelling napkin plus a vest) from the weight when the infant had been weighed partially dressed; and 380 g (a terry-towelling napkin, plus vest, plus a stretchable sleeping-suit) when the infant had been weighed dressed. Where the replies were uncertain we subtracted 380 g from the weight. All the diabetic children had been born "at term" according to their mother’s recollection.
on
1. 2.
The
Drayer, N. M. Archs Dis. Childh. 1974, 49, 616. Sperling, M., Drash, A. Am. J. Dis. Child. 1971, 121,
5.
BLOOD, PLASMA, OR SERUM? SIR,-A recent paper in your journal listing blood analyses for various constituents, mentioning them all as blood this and blood that, stimulates me to write to you, about an increasing carelessness of authors with regard to these tests and, forgive me, perhaps a little lapse on behalf of the editors who review their papers and correct them before publication. May I emphasise that blood samples for analysis for different things in the pathology laboratories mainly comprise three different sources: first, blood-that is, whole bloodwhich is used for substances mainly contained in the red cells (namely, haemoglobin, glutathione, lead) and also for one or two estimations for which there are special reasons for using whole blood not too obvious at first sight (sugar, that is, glucose, is often still done on whole blood, likewise alcohol). The anticoagulant is usually but not always heparin. Secondly, plasma, obtained from anticoagulated blood, is nearly always used now for routine determinations that go through the ’AutoAnalyzer’ system of analysis and this includes urea, electrolytes, cholesterol, and nearly all the common things. For years urea used to be determined on whole blood as it is freely diffusible and the blood urea is only a little less than the plasma urea. But blood has not been used for urea for years now and it is quite wrong, as is so frequently stated, that the blood urea was this or that because the estimation was not done on the blood but on the plasma. Thirdly, there is serum
867 from clotted blood which is sometines used for enzyme studies (although plasma is also used, depending on the laboratory) but is usually used for protein estimations, especially electrophoresis, where the fibrinogen tends’to interfere. Surely it is not asking too much for people to state what has been analysed in any particular case and make quite sure that they get it right. Only in this way can we eventually educate people into sending the right samples to the pathology laboratories for analysis, and also later make sure the results can be compared with those of other workers. While I am on the subject of nomenclature, can I fire off a few more blasts? Namely, that assays for such as "uric acid", "lactic acid", and so on, when determined in blood, deal with compounds always in the form of their salts and should be called urate or lactate. Another old-fashioned survival is the use of the word albumin for the protein that is passed in the
separated
urine, which is usually a mixture of proteins although sometimes mainly comprising albumin. Albumin was the oldfashioned word for protein before it was discovered that there were other sorts of proteins such as globulins, and to use albumin and albuminuria in any medical context which does not correctly describe it puts you back at least fifty years. Those others who have to teach students should surely also be particularly careful in making sure that we teach them consistently to use the right terms, so that expressions such as blood urea and albuminuria do not trip off their tongues (or pens) without any thought of what they are saying (or writing). Medical Unit,
University College Hospital Medical School, London WC1E 6JJ.
C. E. DENT
NEEDLE PUNCTURE OF FETUS DURING AMNIOCENTESIS
SIR,-In connection with the letter of Dr Broome and others (Sept. 27, p. 604) we should like to draw attention to a fetal complication after amniography late in a pregnancy complicated by oligohydramnion, and to suggest a simple aid to prevent this complication. The patient was admitted to the maternity ward in her 39th week of gestation for an induction of labour because of moderate pre-eclamptic toxxmia. Intrauterine growth retardation due to placental insufficiency had been diagnosed and was confirmed by serial placentalhormone determination and by clinical assessment. On admission, the uterus was estimated to be the size of 35 week, and the fetus was at vertex presentation. The head was not engaged. In order to exclude fetal bone and soft-tissue abnormalities amniography was performed. Only a few ml of meconium-stained amniotic fluid could be obtained. 30 ml of 60% ’Urografin’ (Schering) was then instilled into the amniotic cavity. X-rays taken 2 hours later revealed the contrast medium in the fetal pleural space only. The patient began a spontaneous labour 8 hours after the amniography and delivered a 2570 g female, who died soon after delivery from respiratory failure. X-ray of the newborn confirmed that the contrast medium was injected into the right pleural space.
In amniography, avoidance of trauma to the fetus is achieved mainly by repeated amniotic-fluid withdrawal during the procedure. Despite this, fetal injuries have been reported.’2 In pregnancies complicated by oligohydramnion-as in intrauterine growth retardation, postmaturity, or idiopathic-placental-insufficiency syndrome, &c.-none only a few ml of amniotic fluid can be aspirated. The needle can easily be inserted into fetal parts, and the contrast medium injected into the fetal organs. To overcome the possibility of this complication of amniography, we suggest inserting a polyethylene catheter (used in epidural or caudal anaesthesia) through the spinal needle immediately after it has entered the amniotic cavity. If the catheter is inserted easily without any resistance, 2 ml of contrast medium is injected. Then, an X-ray
1 Berner, H. W. Obstet. Gynec. 1967, 29, 200 2 Wiltchik, S. G., Schwartz, R. H., Emich, J.
D. ibid.
1966, 28, 641.
is taken,
to ensure
that the catheter is in the amniotic
cavity. After this, the whole amount of the contrast medium needed is injected safely. Using this technique, we have succeeded in preventing fetal trauma in the course of amniographies done in pregnancies complicated by oligohydramnion. Shaare Zedek
Hospital,
Jerusalem 91000, Israel. *Present address:
D. B. WEISS* Y. ABOULAFIA M. DOLLBERG
Upton Hospital, Slough, Berkshire SL1 2BJ.
VACCINIA TREATMENT OF MELANOMA
SIR,-In their preliminary communication on the use of vaccinia intralesionally before excision of primary melanoma, Dr Everall and his colleagues (Sept. 27, p. 583) discussed the mechanisms which may be involved in the favourable effects they observed. As they indicate, it is especially important that the mechanisms involved be identified and understood, and it is believed that work by others with certain similarities to these trials offers further insight. Reviews’-’ of work on hyperthermia indicate that the pyrexia in these patients partly accounts for the benefits. According to observations reported as early as 1891, the fever of ervsipelas improved or cured patients with cancer. Murkle and Dickson,’ in studies of hyperthermia as an adjuvant to radiotherapy and chemotherapy, found reason to believe that the immune system is stimulated by tumour-cell breakdown and that such stimulation enables the host to fight metastatic lesions. In recent clinical trials, Stehlin et al.4 observed that metastatic lesions in the trunk sometimes disappeared after hyperthermic limb perfusion at 38-8-40-0°C with melphalan for melanoma. They postulated that a "plausible mechanism for such effect could be the stimulation of antitumor immunity of the patient by the antigenic material liberated when melanoma is destroyed in loco ..." In our attemptS to devise a regimen which avoided limb amputation, it was concluded that hyperthermia could be a valuable adjuvant to chemotherapy in osteogenic sarcoma. This conclusion rested on the premise that immune reactions do occur in a significant number of cases after chemothermotherapy of cancerous limbs. The mechanisms of hyperthermic resolution of cancerous lesions and stimulation of specific immune responses are probably also linked to another point mentioned in the preliminary communication-viruses may propagate better in neoplastic than in normal tissue. Neoplastic tissue, like embryonic tissue, is more aqueous than normal adult tissue, and it has been shown that neoplastic tissue has less aqueous structuring than normal tissue.6By using nuclear magnetic resonance to examine the ordered-disordered fractions of water in tissue, normal, preneoplastic, and neoplastic tissue can be distinguished. The nutrient-rich, less-structured neoplastic-cell medium may well provide an environment in which some bacteria and viruses such as vaccinia and B.C.G. would both destroy tumour tissue and produce toxins abundantly. I suggest that research and clinical trials with hyperthermia and the study of water in living systems support the conclusion that the pyrexia observed and the lessened aqueous structure of the neoplastic cell are mechanisms which partly explain the benefits observed. Technology Assessment Group, U.S. Army Missile Research, Development and Engineering Laboratory, Redstone Arsenal, Alabama 35809, U.S.A.
RALPH L. NORMAN
Project Manager
1. Murkle, D. S., Dickson, J. A. Br. J. Cancer, 1973, 27, 307 2. Block, J. B., Zubrod, C. G. Cancer Chemother. Rep. 1973, 57, 373. 3. Vermel, E. M., Kuznetsova, L. B. Probllemy Oncol. U.S.S.R. 1973, 16, 96. 4. Stehlin, J. S., Giovanella, B. C., de Ipolyi, P. D., Muenz, L. R., Anderson, R. F. Surgery, Gynec. Obstet. 1969, 129, 305. 5. Allan, B. D., Norman, R. L. Cancer Chemother. Rep. 1975, 59, 257. 6. Hazewood, C. F., Chang, D. C., Medina, D., Cleveland, G., Nichols, B. L. Proc. nat Acad. Sci. U.S.A. 1972, 69, 1478. 7. Damadian, R., Zaner, K., Hor, D., Di Maio, T., Minkoff, L., Goldsmith, M. Ann. N. Y. Acad. Sci. 1973, 222, 1048.
to
TABLE 11--COMPARISON OF CORRECTED WEIGHTS OF MALF AND OF FEMALE INFANTS WHO LATER DEVELOPED DIABETES WITH CONTROl INFANTS OF THE SAME SEX
malpractice litigation.
The oral
controversy is far from settled. Inthe agents are being overused and misused, more in some countries than in others, but this is the fate of all drugs in common use. It is a problem more likely to be solved by education than legislation. Of course, the public welfare is paramount, and legislative action is sometimes required, but when it is imposed on the basis of shaky evidence and in the face of bona-fide division of opinion it is unacceptable. H. KEEN Department of Medicine, R. J. JARRETT Guy’s Hospital Medical School, London SE1 9RT. J. H. FULLER
hypoglycaemic
contestably,
WEIGHT GAIN IN INFANCY AND SUBSEQUENT DEVELOPMENT OF DIABETES MELLITUS IN CHILDHOOD
SIR,-It has been shown that, at the time of onset of diabetes in childhood, diabetic boys may be taller than average for their age.’ This suggests that an endocrine disorder has preceded overt diabetes by a considerable time. There have also been case-reports of infants with hypoglycaemic episodes developing diabetes mellitus in later childhood.’ These observations led us to investigate the pattern of weight gain in infancy in a group of children who developed diabetes. The 105 families attending our children’s diabetic clinic were sent questionnaires asking them to retrieve information TABLE I.-STATE OF UNDRESS OF DIABETIC CHILDREN WHEN WEIGHED IN
INFANCY, AND WEIOHT DEDUCTED
6
AND
TO ACHIEVE CORRECTED WEIGHTS AT
12
weights of ihese diabetic children in infancy were com40 male and 40 female infants who were born with pared between 38 and 41 weeks of gestation and whose birth-weights were within two standard deviations of the mean. These 80 control infants were randomly selected from a larger group currently under study in Oxford for other purposes. The weights in infancy of the diabetic children and of the control infants are compared in table n. For the males the birth-weights of the two groups are similar; at 6 months the diabetic group is significantly heavier; at 1 year the diabetic group is heavier but this difference does not reach significance. The two groups of female infants are of similar birth-weight; at 6 months the weights are similar; at 1 year the diabetic group is significantly heavier. These data suggest that children who develop diabetes mellitus are heavier at certain stages in infancy. This could be the result of overfeeding. Alternatively it may be an early indication of hormonal imbalance-possibly a relative hyperinsulinism. This work
(J.D.B.) and
supported by the British Diabetic Association M.R.C. programme grant (M.O.).
was
an
Department of Pædiatrics, University of Oxford, John Radcliffe Hospital, Headington, Oxford.
J. D. BAUM M. OUNSTED M. A. SMITH
MONTHS
the weight of their diabetic children at birth, 6 months, and 12 months as recorded on their infant-welfare-clinic cards. We obtained information on the weights in infancy of 13 diabetic girls and 22 diabetic boys. We also asked the parents to record whether the infants had been weighed naked, partially dressed, or dressed when they were weighed, or alternatively to say they were uncertain. These replies are shown in table i. In order to compare these weights with control infants who were weighed naked, we substracted a correction factor 220 g (the weight of a good-quality terry-towelling napkin plus a vest) from the weight when the infant had been weighed partially dressed; and 380 g (a terry-towelling napkin, plus vest, plus a stretchable sleeping-suit) when the infant had been weighed dressed. Where the replies were uncertain we subtracted 380 g from the weight. All the diabetic children had been born "at term" according to their mother’s recollection.
on
1. 2.
The
Drayer, N. M. Archs Dis. Childh. 1974, 49, 616. Sperling, M., Drash, A. Am. J. Dis. Child. 1971, 121,
5.
BLOOD, PLASMA, OR SERUM? SIR,-A recent paper in your journal listing blood analyses for various constituents, mentioning them all as blood this and blood that, stimulates me to write to you, about an increasing carelessness of authors with regard to these tests and, forgive me, perhaps a little lapse on behalf of the editors who review their papers and correct them before publication. May I emphasise that blood samples for analysis for different things in the pathology laboratories mainly comprise three different sources: first, blood-that is, whole bloodwhich is used for substances mainly contained in the red cells (namely, haemoglobin, glutathione, lead) and also for one or two estimations for which there are special reasons for using whole blood not too obvious at first sight (sugar, that is, glucose, is often still done on whole blood, likewise alcohol). The anticoagulant is usually but not always heparin. Secondly, plasma, obtained from anticoagulated blood, is nearly always used now for routine determinations that go through the ’AutoAnalyzer’ system of analysis and this includes urea, electrolytes, cholesterol, and nearly all the common things. For years urea used to be determined on whole blood as it is freely diffusible and the blood urea is only a little less than the plasma urea. But blood has not been used for urea for years now and it is quite wrong, as is so frequently stated, that the blood urea was this or that because the estimation was not done on the blood but on the plasma. Thirdly, there is serum
867 from clotted blood which is sometines used for enzyme studies (although plasma is also used, depending on the laboratory) but is usually used for protein estimations, especially electrophoresis, where the fibrinogen tends’to interfere. Surely it is not asking too much for people to state what has been analysed in any particular case and make quite sure that they get it right. Only in this way can we eventually educate people into sending the right samples to the pathology laboratories for analysis, and also later make sure the results can be compared with those of other workers. While I am on the subject of nomenclature, can I fire off a few more blasts? Namely, that assays for such as "uric acid", "lactic acid", and so on, when determined in blood, deal with compounds always in the form of their salts and should be called urate or lactate. Another old-fashioned survival is the use of the word albumin for the protein that is passed in the
separated
urine, which is usually a mixture of proteins although sometimes mainly comprising albumin. Albumin was the oldfashioned word for protein before it was discovered that there were other sorts of proteins such as globulins, and to use albumin and albuminuria in any medical context which does not correctly describe it puts you back at least fifty years. Those others who have to teach students should surely also be particularly careful in making sure that we teach them consistently to use the right terms, so that expressions such as blood urea and albuminuria do not trip off their tongues (or pens) without any thought of what they are saying (or writing). Medical Unit,
University College Hospital Medical School, London WC1E 6JJ.
C. E. DENT
NEEDLE PUNCTURE OF FETUS DURING AMNIOCENTESIS
SIR,-In connection with the letter of Dr Broome and others (Sept. 27, p. 604) we should like to draw attention to a fetal complication after amniography late in a pregnancy complicated by oligohydramnion, and to suggest a simple aid to prevent this complication. The patient was admitted to the maternity ward in her 39th week of gestation for an induction of labour because of moderate pre-eclamptic toxxmia. Intrauterine growth retardation due to placental insufficiency had been diagnosed and was confirmed by serial placentalhormone determination and by clinical assessment. On admission, the uterus was estimated to be the size of 35 week, and the fetus was at vertex presentation. The head was not engaged. In order to exclude fetal bone and soft-tissue abnormalities amniography was performed. Only a few ml of meconium-stained amniotic fluid could be obtained. 30 ml of 60% ’Urografin’ (Schering) was then instilled into the amniotic cavity. X-rays taken 2 hours later revealed the contrast medium in the fetal pleural space only. The patient began a spontaneous labour 8 hours after the amniography and delivered a 2570 g female, who died soon after delivery from respiratory failure. X-ray of the newborn confirmed that the contrast medium was injected into the right pleural space.
In amniography, avoidance of trauma to the fetus is achieved mainly by repeated amniotic-fluid withdrawal during the procedure. Despite this, fetal injuries have been reported.’2 In pregnancies complicated by oligohydramnion-as in intrauterine growth retardation, postmaturity, or idiopathic-placental-insufficiency syndrome, &c.-none only a few ml of amniotic fluid can be aspirated. The needle can easily be inserted into fetal parts, and the contrast medium injected into the fetal organs. To overcome the possibility of this complication of amniography, we suggest inserting a polyethylene catheter (used in epidural or caudal anaesthesia) through the spinal needle immediately after it has entered the amniotic cavity. If the catheter is inserted easily without any resistance, 2 ml of contrast medium is injected. Then, an X-ray
1 Berner, H. W. Obstet. Gynec. 1967, 29, 200 2 Wiltchik, S. G., Schwartz, R. H., Emich, J.
D. ibid.
1966, 28, 641.
is taken,
to ensure
that the catheter is in the amniotic
cavity. After this, the whole amount of the contrast medium needed is injected safely. Using this technique, we have succeeded in preventing fetal trauma in the course of amniographies done in pregnancies complicated by oligohydramnion. Shaare Zedek
Hospital,
Jerusalem 91000, Israel. *Present address:
D. B. WEISS* Y. ABOULAFIA M. DOLLBERG
Upton Hospital, Slough, Berkshire SL1 2BJ.
VACCINIA TREATMENT OF MELANOMA
SIR,-In their preliminary communication on the use of vaccinia intralesionally before excision of primary melanoma, Dr Everall and his colleagues (Sept. 27, p. 583) discussed the mechanisms which may be involved in the favourable effects they observed. As they indicate, it is especially important that the mechanisms involved be identified and understood, and it is believed that work by others with certain similarities to these trials offers further insight. Reviews’-’ of work on hyperthermia indicate that the pyrexia in these patients partly accounts for the benefits. According to observations reported as early as 1891, the fever of ervsipelas improved or cured patients with cancer. Murkle and Dickson,’ in studies of hyperthermia as an adjuvant to radiotherapy and chemotherapy, found reason to believe that the immune system is stimulated by tumour-cell breakdown and that such stimulation enables the host to fight metastatic lesions. In recent clinical trials, Stehlin et al.4 observed that metastatic lesions in the trunk sometimes disappeared after hyperthermic limb perfusion at 38-8-40-0°C with melphalan for melanoma. They postulated that a "plausible mechanism for such effect could be the stimulation of antitumor immunity of the patient by the antigenic material liberated when melanoma is destroyed in loco ..." In our attemptS to devise a regimen which avoided limb amputation, it was concluded that hyperthermia could be a valuable adjuvant to chemotherapy in osteogenic sarcoma. This conclusion rested on the premise that immune reactions do occur in a significant number of cases after chemothermotherapy of cancerous limbs. The mechanisms of hyperthermic resolution of cancerous lesions and stimulation of specific immune responses are probably also linked to another point mentioned in the preliminary communication-viruses may propagate better in neoplastic than in normal tissue. Neoplastic tissue, like embryonic tissue, is more aqueous than normal adult tissue, and it has been shown that neoplastic tissue has less aqueous structuring than normal tissue.6By using nuclear magnetic resonance to examine the ordered-disordered fractions of water in tissue, normal, preneoplastic, and neoplastic tissue can be distinguished. The nutrient-rich, less-structured neoplastic-cell medium may well provide an environment in which some bacteria and viruses such as vaccinia and B.C.G. would both destroy tumour tissue and produce toxins abundantly. I suggest that research and clinical trials with hyperthermia and the study of water in living systems support the conclusion that the pyrexia observed and the lessened aqueous structure of the neoplastic cell are mechanisms which partly explain the benefits observed. Technology Assessment Group, U.S. Army Missile Research, Development and Engineering Laboratory, Redstone Arsenal, Alabama 35809, U.S.A.
RALPH L. NORMAN
Project Manager
1. Murkle, D. S., Dickson, J. A. Br. J. Cancer, 1973, 27, 307 2. Block, J. B., Zubrod, C. G. Cancer Chemother. Rep. 1973, 57, 373. 3. Vermel, E. M., Kuznetsova, L. B. Probllemy Oncol. U.S.S.R. 1973, 16, 96. 4. Stehlin, J. S., Giovanella, B. C., de Ipolyi, P. D., Muenz, L. R., Anderson, R. F. Surgery, Gynec. Obstet. 1969, 129, 305. 5. Allan, B. D., Norman, R. L. Cancer Chemother. Rep. 1975, 59, 257. 6. Hazewood, C. F., Chang, D. C., Medina, D., Cleveland, G., Nichols, B. L. Proc. nat Acad. Sci. U.S.A. 1972, 69, 1478. 7. Damadian, R., Zaner, K., Hor, D., Di Maio, T., Minkoff, L., Goldsmith, M. Ann. N. Y. Acad. Sci. 1973, 222, 1048.
